Department of Pathology and Laboratory Medicine, University of California, Davis, Medical Center, Sacramento, CA 95817, USA.
J Nutr Biochem. 2012 Jul;23(7):699-705. doi: 10.1016/j.jnutbio.2011.03.012. Epub 2011 Aug 2.
Several lines of evidence support a role for oxidative stress in diabetic complications. Diabetic patients have increased O(2)(-) production in monocytes. Loss of SIRT1 activity may be associated with metabolic diseases such as diabetes. Several studies have shown that SIRT1 can regulate mammalian FOXO transcription factors through direct binding and/or deacetylation. However, interactions between SIRT1 and FOXO under diabetic conditions are unclear. The phytochemical resveratrol has recently gained attention for its protection against metabolic disease. Resveratrol has been shown to increase mitochondrial function by activating SIRT1. In this study, we tested the protective effect of resveratrol on cellular oxidative stress through the SIRT1-FOXO pathway under high-glucose conditions. Human monocytic (THP-1) cells were cultured in the presence of mannitol (osmolar control) or normoglycemic (NG, 5.5 mmol/l glucose) or hyperglycemic (HG, 25 mmol/l glucose) conditions in absence or presence of resveratrol (3 and 6 μmol/l) for 48 h. We first examined SIRT1 activity and oxidative stress in monocytes of Type 1 diabetes mellitus (T1DM) patients compared with healthy controls. In T1DM patients, monocytic SIRT1 expression was significantly decreased and p47phox expression was increased compared with controls. Under HG in vitro, SIRT1 and FOXO3a were significantly decreased compared with NG, and this was reversed by resveratrol treatment, concomitant with reduction in HG-induced superoxide production and p47phox. Under HG, SIRT1 small interfering RNA (siRNA) inhibited FOXO3a, and there was no beneficial effect of resveratrol in siRNA-treated HG-induced cells. Thus, resveratrol decreases HG-induced superoxide production via up-regulation of SIRT1, induction of FOXO3a and inhibition of p47phox in monocytes.
有几条证据表明氧化应激在糖尿病并发症中起作用。糖尿病患者的单核细胞中 O(2)(-)的产生增加。SIRT1 活性的丧失可能与糖尿病等代谢疾病有关。几项研究表明，SIRT1 可以通过直接结合和/或去乙酰化来调节哺乳动物 FOXO 转录因子。然而，在糖尿病条件下，SIRT1 和 FOXO 之间的相互作用尚不清楚。植物化学物质白藜芦醇因其对代谢疾病的保护作用而受到关注。白藜芦醇已被证明通过激活 SIRT1 来增加线粒体功能。在这项研究中，我们在高葡萄糖条件下通过 SIRT1-FOXO 途径测试了白藜芦醇对细胞氧化应激的保护作用。在甘露醇（渗透压对照）或正常血糖（NG，5.5mmol/l 葡萄糖）或高血糖（HG，25mmol/l 葡萄糖）条件下，将人单核细胞（THP-1）细胞在不存在或存在白藜芦醇（3 和 6μmol/l）的情况下培养 48 小时。我们首先比较了 1 型糖尿病（T1DM）患者和健康对照者单核细胞中的 SIRT1 活性和氧化应激。与对照组相比，T1DM 患者单核细胞 SIRT1 表达明显降低，p47phox 表达增加。在体外 HG 条件下，与 NG 相比，SIRT1 和 FOXO3a 明显减少，而白藜芦醇处理可逆转这种情况，同时减少 HG 诱导的超氧产生和 p47phox。在 HG 下，SIRT1 小干扰 RNA（siRNA）抑制 FOXO3a，并且在用 siRNA 处理的 HG 诱导的细胞中，白藜芦醇没有有益作用。因此，白藜芦醇通过上调 SIRT1、诱导 FOXO3a 和抑制 p47phox 来减少 HG 诱导的单核细胞中超氧产生。
